Primary mediastinal lymphoma: diagnosis and treatment options.

Primary mediastinal large B-cell lymphoma (PMBCL) is a unique B-cell lymphoma variant that arises from a putative thymic medulla B cell. It constitutes 2-4% of non-Hodgkin lymphomas and occurs most frequently in young females. PMBCL is characterized by a diffuse proliferation of medium-to-large B cells associated with sclerosis. Molecular analysis shows that PMBCL is a distinct entity compared to other types of diffuse large B-cell lymphomas. PMBCL is characterized by a locally invasive anterior mediastinal bulky mass. The combination of rituximab with CHOP/CHOP-like regimens followed by mediastinal radiation therapy (RT) is associated with a 5-year progression-free survival of 75-85%. However, the role of consolidation RT still remains uncertain. More intensive regimens, such as DA-EPOCH-R without mediastinal RT, have shown very promising results. The conclusive role of PET-CT scan requires prospective studies and there is hope that this may allow to de-escalate RT and accordingly yield reliable prognostic information

Prediction of hearing recovery in sudden deafness treated with intratympanic steroids

The present study aims to obtain a probability model allowing the prediction of the auditory recovery in patients affected by sudden sensorineural hearing loss treated exclusively with intratympanic steroids. A monocentric retrospective chart review of three-hundred eighty-one patients has been performed. A Probit model was used to investigate the correlation between the success of the treatment (marked or total recovery according to Furuashi's criteria), and the delay between the onset of disease and the beginning of therapy. The age of the patients and the audiometric curve shapes were included in the analysis. Results show that delay is negatively correlated with the variable success. Considering the entire sample, each day of delay decreases by 3% the probability of success. The prediction model shows that for every day that passes from the onset of the disease the probability of success declines in absence of the medical treatment, hence we conclude that early treatment is strongly recommended

Discovery of a Novel Small Molecule Inhibitor Targeting the Frataxin/Ubiquitin Interaction via Structure-Based Virtual Screening and Bioassays

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the mitochondrial protein frataxin. Here, we report findings that frataxin is degraded via the ubiquitin-proteasomal pathway and that it is ubiquitinated at residue K147 in Calu-6 cells. A theoretical model of the frataxin-K147/Ub complex, constructed by combining bioinformatics interface predictions with information-driven docking, revealed a hitherto unnoticed, potential ubiquitin-binding domain in frataxin. Through structure-based virtual screening and cell-based assays, we discovered a novel small molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation. (+)-11 was synthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay. Follow-up scaffold-based searches resulted in the identification of a lead series with micromolar activity in disrupting the frataxin/Ub interaction. This study also suggests that frataxin could be a potential target for FRDA drug development

Seismic rehabilitation of cultural heritage masonry buildings with unbonded fiber reinforced elastomeric isolators (U-FREIs) \u2013 A case of study

In order to assess the structural behavior and to evaluate the seismic vulnerability of masonry structuresof relevant historical and artistic significance, which is a widespread building type in Italy and in the world,an historical masonry church is analyzed under earthquake loading. Linear and non-linear analyses areperformed on the finite element models of the structure. From these analyses it is pointed out that thestructure does not behave elastically in its existing condition even when subjected to the frequent designearthquake (81% probability of being exceeded over 50 years). Two traditional rehabilitation methods arestudied: the placement of a rigid diaphragm which connects the top of the masonry walls only enclosingthe church entrance area and the placement of a rigid diaphragm which connects the tops of all masonrywalls. None of the traditional method is sufficient for the structure to survive basic design earthquake(10% probability of being exceeded over 50 years). Hence an advanced seismic retrofit solution usinginnovative carbon fiber reinforced elastomeric isolators is proposed. The proposed intervention consistsin the installation of six Unbonded Fiber-Reinforced Elastomeric Isolators (U-FREI) and six Flat SurfaceSliders (FSS) as passive protective devices besides the placement of a rigid diaphragm which connects thetops of all masonry walls. The process of installation of the devices is illustrated. The use of the proposedsolution leads to a remarkable enhancement of the seismic response capacities of the structure; indeeda general elastic response under the Basic Design Earthquake (BDE) is attained

5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-b-synthase in colon cancer cells lacking p53

Recent findings revealed in cancer cells novel stress response pathways, which in response to many chemotherapeutic drugs causing nucleolar stress, will function independently from tumor protein p53 (p53) and still lead to cell cycle arrest and/or apoptosis. Since it is known that most cancers lack functional p53, it is of great interest to explore these emerging molecular mechanisms. Here, we demonstrate that nucleolar stress induced by 5-fluorouracil (5-FU) in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 (rpL3) as proapoptotic factor. rpL3, as ribosome-free form, is a negative regulator of cystathionine-β-synthase (CBS) expression at transcriptional level through a molecular mechanism involving Sp1. The rpL3-CBS association affects CBS stability and, in addition, can trigger CBS translocation into mitochondria. Consequently apoptosis will be induced through the mitochondrial apoptotic cell death pathway characterized by an increased ratio of Bax to Bcl-2, cytochrome c release and subsequent caspase activation. It is noteworthy that silencing of CBS is associated to a strong increase of 5-FU-mediated inhibition of cell migration and proliferation. These data reveal a novel mechanism to accomplish p53-independent apoptosis and suggest a potential therapeutic approach aimed at upregulating rpL3 for treating cancers lacking p53

The Lorentz force between D0 and D6 branes in string and M(atrix) theory

We use different techniques to analyze the system formed by a D0 brane and a D6 brane (with background gauge fields) in relative motion. In particular, using the closed string formalism of boosted boundary states, we show the presence of a term linear in the velocity, corresponding to the Lorentz force experienced by the D0 brane moving in the magnetic background produced by the D6 brane. This term, that was missed in previous analyses of this system, comes entirely from the R-R odd spin structure and is also reproduced by a M(atrix) theory calculation.Comment: 13 pages, plain LaTeX; some clarifying comments and a reference adde

Design optimisation problems of stress corrosion in welded joints in 7000 alloy

The use of thick plates of high-strength aluminium alloys, in specific welded structures, gives the designer many optimisation problems concerning the prediction and elimination of brittle fracture in the welded joints, caused by stress corrosion in the zone next to the weld beads. The Istituto Sperimentale dei Metalli Leggeri has faced and worked out these problems, in parallel with investigations of a metallurgical nature concerning the microstructural characteristics of the base metal in the heat affected zone (HAZ) next to the weld.The results of these studies enabled us to define, with the aid of appropriate structural calculation techniques, some design schemes which ensure a high resistance to brittle fracture by stress corrosion in special welded joints. This paper investigates and discusses such problems

Integrated calcareous plankton biostratigraphy of selected Miocene successions in the Northern Calabria (Italy)

An integrated calcareous plankton biostratigraphic approach on six sections cropping out in Northern Calabria allowed to define a revised chronostratigraphic framework for Tortonian-Messinian deposits. Four sections have been investigated in the Amantea Basin (Timpone Napoli, Vallone Salina, Case Vespano, and Cozzo Salice) and two in the Rossano Basin (Vallone Casino and Cozzo Sant'Isidoro). Biostratigraphic analyses have been based on quantitative counting of planktonic foraminifers and semiquantitative counting of nannofossils. The Timpone Napoli and Vallone Salina sections are Late Tortonian in age and referable to the Globorotalia suterae Zone. In terms of nannofossils zonal scheme these sections fall within the Coccolithus pelagicus - Amaurolithus primus Zones. The Case Vespano and Cozzo Salice sections can be ascribed to the Messinian. The Case Vespano section is wholly characterized by the common occurrence of Globorotalia miotumida group. The co-occurrence of Amarolithus delicatus, A. cf. amplificus,. and Reticulofenestra rotaria confirms a Messinian age. The lower part of the Cozzo Salice section is rich of Gt. conomiozea, while its middle and the upper part is barren in planktonic foraminifers. In the Vallone Casino and Cozzo Sant'Isidoro sections the Tortonian-Messinian boundary corresponds to the first occurrence (FO) of Gt. miotumida group (sensu Hilgen et al., 2000), just above the first occurrence of A. delicatus. Biostratigraphic data allowed to correlate the Messinian silty layers of Amantea Basin with the coeval diatomitic beds of Rossano Basin indicating that the two areas, during the Messinian, had different paleogeographic and palaeoecological evolution